Solid form, crystalline form, and crystal form a of FXR agonist, and preparation method and application thereof

Abstract

Disclosed are a solid form, a crystalline form, and crystal form A of a compound of formula (I) used as an FXR agonist, and a preparation method therefor. Also comprised is an application of the compound of formula (I) in preparation of a medication for treating nonalcoholic steatohepatitis (NASH).

What is claimed is: 
     
       1. A crystalline form of a compound of formula (I), which is crystal form A, characterized by X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles of 12.72±0.2°, and 25.27±0.2°; 
       
         
           
           
               
               
           
         
       
     
     
       2. The crystal form A of the compound of formula (I) according to  claim 1 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 24.18±0.2°, and 25.27±0.2°. 
     
     
       3. The crystal form A of the compound of formula (I) according to  claim 2 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 20.38±0.2°, 22.60±0.2°, 23.80±0.2°, 24.18±0.2°, and 25.27±0.2°. 
     
     
       4. The crystal form A of the compound of formula (I) according to  claim 3 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 13.67±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 20.38±0.2°, 22.60±0.2°, 23.80±0.2°, 24.18±0.2°, 25.27±0.2°, and 26.57±0.2°. 
     
     
       5. The crystal form A of the compound of formula (I) according to  claim 4 , wherein the X-ray powder diffraction pattern is as shown in  FIG.  1   . 
     
     
       6. The crystal form A of the compound of formula (I) according to  claim 1 , wherein the X-ray powder diffraction pattern is as shown in  FIG.  5   . 
     
     
       7. The crystal form A of the compound of formula (I) according to  claim 1 , characterized by a differential scanning calorimetry curve having a starting point of the endothermic peak at 223.58° C.±3° C. 
     
     
       8. The crystal form A of the compound of formula (I) according to  claim 7 , wherein the differential scanning calorimetry curve is as shown in  FIG.  2   . 
     
     
       9. The crystal form A of the compound of formula (I) according to  claim 1 , characterized by a thermogravimetric analysis curve having a weight loss of up to 0.7427%±0.2% at 111.29° C.±3° C. and up to 3.6977%±0.2% at 202.79° C.±3° C. 
     
     
       10. The crystal form A of the compound of formula (I) according to  claim 9 , wherein the thermogravimetric analysis curve is as shown in  FIG.  3   . 
     
     
       11. A method for preparing the crystal form A of the compound of formula (I) according to  claim 1 , comprising:
 (a) adding the compound of formula (I) to a solvent; 
 (b) stirring at 30 to 50° C. for 40 to 55 hours; and 
 (c) centrifugating, and then volatilizing the solvent to give the crystal form A of the compound of formula (I); 
 wherein the solvent is alcohol, tetrahydrofuran, water, acetone, acetonitrile, ethyl acetate, a mixed solvent of alcohol and water, or a mixed solvent of acetone and water. 
 
     
     
       12. The preparation method according to  claim 11 , wherein the alcohol is selected from methanol, ethanol, isopropanol and n-propanol. 
     
     
       13. The preparation method according to  claim 11 , wherein the solvent is a mixed solvent of alcohol and water, wherein the volume ratio of alcohol to water is 1:0.6 to 1:1.5. 
     
     
       14. The preparation method according to  claim 11 , wherein the solvent is a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is 1:1.5 to 1:2.5. 
     
     
       15. A method of treating a FXR-related disease selected from metabolic syndrome, hepatobiliary disease, type 2 diabetes, and non-alcoholic fatty liver disease in a subject, comprising administering to the subject the crystal form A of the compound of formula (I) according to  claim 1 . 
     
     
       16. The method according to  claim 15 , wherein the FXR-related disease is non-alcoholic fatty liver disease. 
     
     
       17. A method of improving hepatic steatosis, improving hepatic function, reducing hepatic damage, or improving hepatic fibrosis in a subject, comprising administering to the subject the crystal form A of the compound of formula (I) according to  claim 1 .